Alzheimer's Disease is a common form of dementia associated with memory loss, intellectual function decline, depression, and disorientation. Alzheimer's Disease affects more than 5 million people in the United States and costs over $200 billion every year. (Alzheimer's Association, The Journal of the Alzheimer's Association (2012) 8: 131-168.) It is found in 13% of the population over the age of 65 and 45% of the population over the age of 85. (Alzheimer's Association, The Journal of the Alzheimer's Association (2012) 8: 131-168.) With a rapidly aging American population, prevalence of Alzheimer's Disease is expected to increase 2.5-fold to 13 million people in the United States in the next few decades. (Hebert et al., Arch Neurol (2003) 60: 1119-1122). Alzheimer's Disease will continue to be a major and expensive health crisis.
Alzheimer's Disease is typified by increased deposition of amyloid beta plaques and neurofibrillary tangles in the brain. More than 95% of the cases are considered “sporadic” and affect individual older than 65 years of age (late-onset). These cases are distinguished from the rare, early-onset, genetically-linked cases where production and deposition of amyloid beta plaques is higher. (Bateman et al., Alzheimer's Res Ther. (2011) 3: 1-13). Individuals with late-onset Alzheimer's Disease produce amyloid beta plaques at a normal rate and level, but have a reduced ability to clear the amyloid beta plaques from the brain. (Mawuenyega, et al., Science (2010) 330: 1774.)
Apolipoprotein-E (apoE) is a cholesterol- and lipid-carrier that has been implicated in aging, atherosclerosis and several neurological diseases including Alzheimer Disease. (Mahley, et al., J Clin Invest (2006) 116: 1226-9, Thorngate, et al., Vasc Biol (2000) 20: 1939-45, Fullerton, et al., Exp Neurol (2001) 169: 13-22, Ji, et al., Neuroscience (2003) 122: 305-15, and Dergunov, et al., Biochemistry (Mosc) (2006) 71: 707-12.) ApoE genotype is the biggest risk factor for Alzheimer's Disease and may account for 60-90% of the genetic variance associated with Alzheimer's Disease. (Raber, et al., Neurobiol Aging (2004) 25: 641-50.)
There are three common isoforms (alleles) of apoE in humans: apoE2, apoE3, and apoE4—which contribute to the pleiotropic effects observed in human cognition and neurodegenerative diseases. (Bales, et al., Proc Natl Acad Sci USA (1999) 96: 15233-3, Holtzman, et al., J Clin Invest (1999) 103: 15-21.) Several lines of evidence support the idea that the human apoE4 is hypofunctional and is considered to be the “bad” apoE, while apoE3 is the most common isoform and is considered to be the “normal” apoE. (Mahley, et al., Proc Natl Acad Sci USA (2006) 95:7585-90, and Hauser, et al., Prog Lipid Res (2011) 50: 62-74.) The risk for Alzheimer's Disease is two- and seven-fold higher in subjects that are heterozygous and homozygous, respectively, for apoE4. (Corder, et al., Science (1993) 261:921-3.) The age of disease onset is also accelerated by 6-8 years for each inherited copy of apoE4. (Corder, et al., Science (1993) 261:921-3.) Several groups consider the apoE4 allele to be detrimental because the apoE4 protein aggregate with amyloid beta plaques more readily than the apoE3 protein and apoE4 is less effective at clearing the amyloid beta plaques from the brain (Tokuda, et al., Biochem J (2000) 348: 359-65, Castellano, et al., Sci Transl Med (2011) 3:895-7, and Buttini, et al., Neuroscience (2000) 97:207-10.). These and other neurodegenerative effects have led some to conclude that apoE4 protein behaves like a “dominant-negative mutant,” is “a causative factor” in Alzheimer's Disease pathogenesis, and a “neglected opportunity” for treatment of Alzheimer's Disease. Thus, there is a strong interest in the biomedical community to find therapies that can reduce apoE levels. These therapies are of value to all individuals, and especially to subjects that have apoE4 allele(s).
Unlike humans, most other mammals have only one common apoE allele (Mahley and Rall, Annu Rev Genomics Hum Genet (2000) 1:507-37.) Increase in levels of murine apoE in a mouse model of Alzheimer's Disease by Bexarotene, an FDA-approved cancer drug, has been considered to be of therapeutic relevance because of the associated clearance of soluble amyloid beta as well as amyloid beta plaques. (Cramer, et al., Science (2012) 335: 1503-6.) However, more than half of the subjects suffering from Alzheimer's Disease have at least one copy of the “bad” apoE4 allele, and thus there is the need for inhibiting apoE gene expression in these individuals. (Raber, et al., Neurobiol Aging (2004) 25: 641-50, Corder, et al., Science (1993) 261:921-3.)
Since the American population is aging, and the percentage of American people with Alzheimer's Disease is expected to increase, there is the need to further develop small organic molecules that can be easily administered to slow or stop the progression of the disease. Since apoE4 protein is detrimental to clearing amyloid beta plaques from brain tissue, any developed organic molecule that can be administered to people to stop the expression of apoE4 would likely have implications in Alzheimer's Disease treatments.